Neural Control of Choroidal Function

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PROJECT SUMMARY In primates, including humans, the macula and especially the fovea, is critical for high-acuity vision. The metabolic needs of the fovea and macula are primarily met by the choriocapillaris, the capillary network of the choroid located immediately behind Bruch’s membrane. There is considerable evidence that compromised choroidal perfusion contributes to many eye diseases, such as age-related macular degeneration and diabetic retinopathy, that affect these retinal regions. Importantly, choroidal blood flow is substantially controlled by inputs from the parasympathetic nervous system. However, the parasympathetic circuitry controlling the choroidal vasculature in primates is very poorly understood. The precise locations of the pre- and postganglionic parasympathetic motoneurons supplying the choroid, as well as their premotor inputs have not been established, nor have the functional roles of these neurons been fully defined. Therefore, the overall goal of this proposal is to determine the location and function of the parasympathetic circuits controlling the choroidal vasculature in non-human primates. We propose to perform neuroanatomical, electrophysiological, and pharmacological experiments to address these questions. Specifically, in Aim 1, we will use retrograde tracers, both conventional and trans-synaptic, to identify the motor and premotor circuitry controlling the parasympathetic innervation of the choroid. In the functional part of the study, we will use infrared (IR) laser doppler flowmetry, IR laser speckle flowgraphy (LSFG), and optical coherence tomography (OCT)/OCT angiography (OCTA) to measure the choroidal vasculature. Specifically, in Aim 2, we will study the effects on the choroidal vasculature of modulating preganglionic motoneuron activity by electrical microstimulation and of modulating retinal activity by light. In Aim 3A, we hypothesize that pharmacological inactivation of preganglionic motoneurons reduces overall choroidal blood flow and thickness in darkness, reduces choroidal blood flow compensation for changes in blood pressure, and eliminates luminance induced changes in the choroidal vasculature. In Aim 3B, we hypothesize that electrolytic or chemical lesions of preganglionic motoneurons will result in reduced choroidal blood flow. In the long term, we hypothesize that the retina will show evidence of outer segment loss and inflammatory markers. We will non-invasively assess retina, retinal pigment epithelium, and choroid health in life by OCT/OCTA, LSFG, and electroretinogram (ERG)/multifocal ERG. We will further assess retinal health postmortem by retinal histology. The proposed experiments will constitute the first extensive and systematic investigation of the circuitry and role of the parasympathetic, preganglionic neurons controlling blood flow in the choroidal vasculature of a primate. These results will set the stage for future studies in which this circuitry is modulated in order to improve the survival of central vision in human macular degeneration.